Palladium-catalysed cross-coupling reactions in supercritical carbon dioxide

Article abstract of DOI:10.1039/b106808c

Heck and Suzuki reactions proceed in good yield in supercritical carbon dioxide in the presence of palladium acetate and tri-tert-butylphosphine with both free and polymer-tethered substrates.

Full text of DOI:10.1039/b106808c

View Article Online / Journal Homepage / Table of Contents for this issue
Palladium-catalysed cross-coupling reactions in supercritical carbon
dioxide
Tessa R. Early,a Richard S. Gordon,a Michael A. Carroll,a Andrew B. Holmes,*a Richard E.
Shuteb and Ian F. McConveyc
a Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge,
Pembroke Street, Cambridge, UK CB2 3RA. E-mail: abh1@cam.ac.uk; Fax: +44 1223 334866;
Tel: +44 1223 334370;
b AstraZeneca Research and Development, Alderley Park, Macclesfield, Cheshire, UK SK10 4TG
c
AstraZeneca Process Research and Development, Macclesfield, Cheshire, UK SK10 2NA
Received (in Cambridge, UK) 27th July 2001, Accepted 29th August 2001
First published as an Advance Article on the web 19th September 2001
Heck and Suzuki reactions proceed in good yield in
supercritical carbon dioxide in the presence of palladium
acetate and tri-tert-butylphosphine with both free and
polymer-tethered substrates.
solubilise the palladium complex. To date, although the use of
non-fluorinated phosphine ligands has been contemplated, the
results have been disappointing, and inferior to the comparable
fluorinated system. Rayner8 reported added advantages in using
palladium trifluoroacetate with commercial phosphines and
metallocycles in the Heck reaction. Arai and co-workers
communicated a Heck reaction in scCO2 using a water soluble
catalyst in a biphasic system, in which phase-transfer additives
such as ethylene glycol afforded an increased reaction yield.9
Very recently Bannwarth10 described the application of per-
fluoro-tagged triphenylphosphine derivatives in the Stille
reaction. Significantly, triphenylphosphine itself was also used
as a ligand, with lower overall yields than the fluoro-analogue,
but still an improvement over the previously reported work.7
Tri-tert-butylphosphine [P(t-Bu)3] has been shown by Fu to
be a highly active catalyst in a variety of palladium-catalysed
coupling reactions.11,12 We now show that the combination of
palladium acetate with P(t-Bu)3 very effectively catalyses Heck
and Suzuki reactions of aryl halides in scCO2. The solubility of
triethylphosphine in scCO2 has previously been noted.13
We first tested P(t-Bu)3 as a ligand in the Heck reaction, a
system with which we had previous experience.6 (Table 1,
entries 1a and b). Initial results were promising, and the
application of this completely non-fluorous system to the
The synthesis of organic molecules in the absence of volatile
organic solvents remains an important industrial goal and the
use of alternative reaction media in synthetic chemistry has
attracted widespread attention. Supercritical carbon dioxide
(scCO2) has recently attracted much interest as an environmen-
tally benign alternative to many toxic organic solvents.1–3 It is
non-toxic, inexpensive, universally available and affords facile
separation from products by simple depressurisation. However,
its practical use has been limited by its solvent power. Although
scCO2 will dissolve most non-polar compounds of low
molecular mass, many catalysts, substrates and reagents are
only poorly soluble.
Heck and Suzuki reactions have evolved into one of the most
versatile families of reactions, as illustrated in the recent
literature.4,5 Their application in scCO2 media was initially
hindered by the poor solubilities of commercially available
metal catalysts. In 1998 we6 and Tumas7 independently
reported the first palladium-catalysed carbon–carbon coupling
reactions in scCO2 using fluorinated phosphine ligands to
Table 1 Heck and Suzuki reactions in scCO2 using the Pd(OAc)2–P(t-Bu)3 catalytic systema
Entry
Substrate 1
Substrate 2
Product
Base
T/°C
Yieldb (%)
1a
1b
NEt3
DIPEA
100
100
77
92c
2
DIPEA
DIPEA
Me2N(CH2)6NMe2 120
Bu4NOAc
Et4NOAc
100
100
68
3a
3b
3c
3d
73
76
69d
70d
100
100
4a
4b
DIPEA
Cs2CO3
100
100
54
52
5a
5b
DIPEA
DIPEA
80
80
67e
70e
6
DIPEA
80
98ce
a All reactions were conducted in scCO2 over a 16 h period with 5 mol% palladium and a two-fold molar ratio of phosphine to palladium acetate unless
otherwise stated. b Isolated yield by column chromatography. c 10 mol% palladium. d HPLC yield e Isolated yield after base cleavage from resin. DIPEA
(Hünig’s base) is N,N-diisopropylethylamine.
1966
Chem. Commun., 2001, 1966–1967
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106808c

View Article Online
promoting C–C bond forming reactions in scCO2. We have
applied this system to the first example of polymer-supported
reactions in scCO2.
We thank the EPSRC, AstraZeneca, the Commission of the
EU (Brite-Euram Contract BRRT-CT98-5089 ‘RUCADI’) and
the Isaac Newton Trust, Cambridge for generous financial
support. We thank EPSRC for provision of the Swansea Mass
Spectrometry Service.
Scheme 1 Reagents and conditions: (i) 5 mol% Pd(OAc)2, 10 mol%
phosphine 1, NEt3, scCO2, 100 °C, 40 h. (ii) NaOMe, MeOH, THF.
Suzuki reaction was also successful (entries 2–4). The yields for
these reactions are not yet optimised.†
Both aryl iodides and bromides underwent the Suzuki
reaction, although lower yields were obtained with the less
reactive bromide coupling partners. A variety of different bases
were investigated and shown to be effective in scCO2.
Surprisingly these reactions proceeded effectively in the
presence of solid tetraalkylammonium acetate salts without
addition of any other base. Jeffrey has reported the use of
alkylammonium salts for the Heck reaction in conventional
solvents.14 In addition, Bannwarth reported the use of tetra-n-
butylammonium chloride in a Stille reaction in scCO2.10 We
have found in related cross coupling reactions that the acetate is
superior.15
Solid phase organic synthesis carried out on a substrate
bound to a solid, typically polymeric, support continues to be an
area of intense study. The application of solid phase synthesis to
palladium-catalysed reactions has been the subject of recent
reviews.16,17 Conducting reactions on a solid support provides
an attractive and practical method for clean and efficient
synthetic preparations, allowing convenient separation of
products from the reaction mixture and forming the basis of
combinatorial chemistry. Reactions using polymer supports
require the use of a solvent that will swell the polymer and
expose reactive sites. The ability of scCO2 to plasticise
polymers has been exploited in a number of applications
including polymer impregnation, formation of blends and
particle formation.18 We expected therefore that scCO2 would
provide a good swelling solvent for polymer supported
reagents, allowing access to reactive sites and reducing the
amount of excess reagent required to give acceptable cov-
erage.
We now report the successful application of solid supported
substrates for palladium catalysed Heck and Suzuki couplings
in scCO2. The first pilot reaction employed a catalytic system of
palladium acetate with the highly fluorinated phosphine
PhP(CH2CH2C6F13)2, 1 (Scheme 1).6 REM resin19 underwent a
Heck reaction with iodobenzene and the modified resin was
then cleaved under basic conditions to give (E)-methyl
cinnamate in 74% yield over the two steps.
After this initial success we then extended the palladium
acetate–P(t-Bu)3 catalytic system to substrates immobilised on
a polymer resin. The Suzuki reaction was applied to a
functionalised Merrifield resin and proceeded in good yield,
comparable to reactions off resin (Table 1, entries 5a and b). The
Heck reaction on REM resin19 gave a near-quantitative yield
(entry 6). These results clearly demonstrate the successful
application of the palladium-mediated cross-coupling method-
ology to a heterogeneous system, and form to our knowledge the
first example of the use of polymer supported synthesis in
scCO2.
Notes and references
† Typical procedure for the Suzuki reaction in supercritical carbon dioxide:
palladium(II) acetate, (11 mg, 0.05 mmol) and tolylboronic acid (204 mg,
1.5 mmol) were placed in a 10 cm3 stainless steel cell, which was taken into
a nitrogen atmosphere (glove-box) where tri-tert-butylphosphine (20 mg,
0.1 mmol) was added, and the cell was sealed, and removed from the glove-
box. Iodobenzene (0.204 g, 1 mmol) and N,N,NA,N'A-tetramethylhexane-
1,6-diamine (0.172 g, 1 mmol) were injected through the inlet port. The cell
was then connected to the CO2 line and charged with CO2 (99.9995%—fur-
ther purified over an Oxisorb® catalyst) to approximately 880 psi (volume
ca. 5 cm3 liquid carbon dioxide). The cell was heated to 100 °C and the
pressure was adjusted to 3000 psi by the addition of CO2. The reagents were
maintained at this temperature and pressure for 16 h and the cell was then
allowed to cool to room temperature. The contents of the cell were vented
into ethyl acetate (100 cm3), and once atmospheric pressure had been
reached the cell was opened and washed out with further ethyl acetate (20
cm3). The combined organic fractions were concentrated in vacuo to give
the crude product which was adsorbed onto a flash silica column using
CH2Cl2 and eluted with hexane to give a white crystalline solid (128 mg,
76%), mp 47–48 °C (lit.20 49–50 °C) dH (400 MHz; CDCl3) 7.59 (2 H, dd,
oA-Ph, J 7.8, 1.2 Hz), 7.51 (2H, d, m-Ar, J 8.1 Hz), 7.44 (2 H, dd, mA-Ph, J
7.8, 7.35 Hz), 7.33 (1 H, td, pA-Ph, J 7.35, 1.2 Hz), 7.26 (2H, d, o-Ar, J 8.1
Hz), 2.41 (3 H, s, Ar-CH3).
1 R. S. Oakes, A. A. Clifford and C. M. Rayner, J. Chem. Soc., Perkin
Trans. 1, 2001, 917.
2 J. A. Darr and M. Poliakoff, Chem. Rev., 1999, 99, 495.
3 P. G. Jessop and W. Leitner, Chemical Synthesis Using Supercritical
Fluids, Wiley-VCH, Weinheim, 1999.
4 I. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009.
5 A. Suzuki, J. Organomet. Chem., 1999, 576, 147.
6 M. A. Carroll and A. B. Holmes, Chem. Commun., 1998, 1395.
7 D. K. Morita, D. R. Pesiri, S. A. David, W. H. Glaze and W. Tumas,
Chem. Commun., 1998, 1397.
8 N. Shezad, R. S. Oakes, A. A. Clifford and C. M. Rayner, Tetrahedron
Lett., 1999, 40, 2221.
9 B. M. Bhanage, Y. Ikushima, M. Shirai and M. Arai, Tetrahedron Lett.,
1999, 40, 6247.
10 T. Osswald, S. Schneider, S. Wang and W. Bannwarth, Tetrahedron
Lett., 2001, 42, 2965.
11 A. F. Littke and G. C. Fu, J. Org. Chem., 1999, 64, 10.
12 A. F. Littke and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 6989 and
references cited therein.
13 I. Bach and D. J. Cole-Hamilton, Chem. Commun., 1998, 1463.
14 T. Jeffrey, Tetrahedron, 1996, 30, 10113.
15 T. R. Early, R. S. Gordon, M. A. Carroll, A. B. Holmes, R. E. Shute and
I. F. McConvey, manuscript in preparation.
16 C. L. Kingsbury, S. J. Mehrman and J. M. Takacs, Curr. Org. Chem.,
1999, 3, 497.
17 R. Franzen, Can. J. Chem., 2000, 78, 957.
18 A. I. Cooper, J. Mater. Chem., 2000, 10, 207 and references cited
therein.
19 J. R. Morphy, Z. Rankovic and D. C. Rees, Tetrahedron Lett., 1996, 37,
In summary we have shown that the non-fluorinated
palladium acetate–P(t-Bu)3 catalyst system is highly active in
3209.
20 M. S. C. Rao and G. S. K. Rao, Synthesis, 1987, 231.
Chem. Commun., 2001, 1966–1967
1967